The use of plant extracts in Traditional Chinese Medicine (TCM) can be traced back to 6000 years ago (Solecki and Shanidar, 1975). In recent years, there has been a burgeoning use of plant extracts in TCM for modern drug discovery (Graziose et al., 2010). These plant extracts are used for a variety of purposes including health improvement, beauty, and nutritional supplementation, as well as prevention and treatment of diseases, including diabetes and cancer (Graziose et al. 2010).
Carica papaya is one of the candidate plants. It has been reported to have medicinal properties towards various diseases including dengue fever (Ahmad et al., 2011), wound healing (Mahmood et al., 2005) and asthma (Canini et al., 2007). Extracts from Carica papaya also claimed to have anti-cancer properties (Morimoto et al., US Patent Application No. 20080069907). These investigators, however, did not indicate the specific mechanisms that were involved in the anti-cancer effects, nor did they indicate that the age of the plant could have any effect on the efficacy of the treatment.
Oxygen homeostasis is a critical element for physiological well-being of the human body. Limited oxygen supply, termed hypoxia, plays a major role in the pathobiology of solid tumors. Hypoxia and oxidative stress pathways are associated with various human disorders, including inflammatory diseases, vascular diseases, cancer and infectious diseases. Cells in hypoxic regions of tumors are more resistant to radiation and chemotherapy (Brown. 2000). They are also more resistant to cell death signaling (Seol et al., 2009). Master regulators of cell survival under hypoxia are the hypoxia-inducible factors (HIFs), HIF-1 and HIF-2. These transcription factors regulate several processes vital for the cells to survive the hypoxic conditions (Semenza, 2011; Miyara et al. 2011). Since these cancer cells have altered metabolic mechanisms for survival under hypoxia, we conjectured that their responses to plant extracts also will be different from normoxic cancer cells. Even though HIF-inhibitory drugs have been approved by the US-FDA for clinical use (Xia et al., 2012), their undesirable side effects are still problematic (Sanchez et al., 2012; Yamaguchi et al., 2012). Due to the limited number of drug candidates in the pipeline and the adverse side effects of the approved ones, identification and development of candidate drug inhibitors that target the HIF-1 pathway are urgently needed.